Understanding the interplay between coxsackievirus and the host ubiquitin-proteasome system

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Positive RNA viruses, which have all their genetic information in a single positive-strand of RNA, encompass more than one-third of all virus genera and cause various diseases in plants, animals, and humans. To ensure successful infection, viruses in this family have evolved to exploit the host cellular machinery, such as the ubiquitin-proteasome system (UPS), to support their lifecycle. The proteasome is a large cellular complex that breaks down unwanted or damaged proteins that have been marked with a small protein called ubiquitin. Apart from influencing the stability of the target proteins, attachment of ubiquitin can also change the function/activity of substrate proteins without targeting them for degradation. In this research program, we will use coxsackievirus as a model organism to understand how positive-strand RNA viruses interact with the host UPS to achieve successful production. Our hypothesis is that coxsackievirus subverts this system to support its infection by regulating the abundance and function of host and viral proteins. We previously discovered that depletion of ubiquitin or inhibition of the proteasome activity markedly reduces viral replication, suggesting an important role for the UPS in coxsackieviral infection. In addition, we found that ubiquitin-independent proteasome-mediated degradation is also utilized by coxsackievirus to promote viral growth. However, the exact mechanism of action has not been elucidated. Here we propose to study the molecular basis responsible for the dysregulation of the UPS as a consequence of coxsackievirus infection and the underlying mechanisms by that control viral replication. Specifically, we will combine the use of cutting-edge proteomics approaches with conventional molecular and cellular technologies to investigate how viral proteins manipulate the UPS and to identify the critical enzymes and target proteins within the UPS that regulate viral infectivity. We will also dissect out the functional significance of ubiquitin-mediated modification of viral proteins. This research explores a novel proteasome-based mechanism that will change our understanding of how viruses subvert the host cellular machinery. Knowledge gained from this program will also have broader implications for the study of host-pathogen interaction of other viruses in the same family.